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1.
JCO Precis Oncol ; 8: e2400334, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39447095

RESUMO

PURPOSE: Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene NUTM1 on chromosome 15q14. Co-occurring alternations have not been fully characterized. METHODS: We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris). RESULTS: While NC is driven by NUTM1 fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of NUTM1 and co-occurring gene mutations. RNA sequencing analysis showed increased MYC pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years. CONCLUSION: To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High MYC pathway activity in NC supports ongoing trials targeting MYC suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.


Assuntos
Proteínas Nucleares , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Proteínas Nucleares/genética , Adulto , Feminino , Proteínas de Neoplasias
2.
Explor Target Antitumor Ther ; 5(4): 931-954, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39280253

RESUMO

Non-small cell lung cancer (NSCLC) that is operable still carries a high risk of recurrence, approaching 50% of all operable cases despite adding adjuvant chemotherapy. However, the utilization of immunotherapy and targeted therapy moving beyond the metastatic NSCLC setting and into early-stage perioperative management has generated tremendous enthusiasm and has been practice-changing. Adjuvant atezolizumab in NSCLC first demonstrated a clinical benefit with an immune checkpoint inhibitor. Then, with studies studying a significant benefit in major pathologic response in surgical patients treated preoperatively with immunotherapy compared to only chemotherapy, neoadjuvant nivolumab and chemotherapy were evaluated and showed significant event-free survival benefit leading to subsequent studies evaluating perioperative immunotherapy and chemotherapy. Meanwhile, with regards to targeted therapies, adjuvant osimertinib in EGFR-mutated NSCLC and adjuvant alectinib in ALK-rearranged NSCLC have both received regulatory approvals following demonstrated clinical benefit in clinical trials. With rapidly evolving changes in the field, new combinations such as multiple immunotherapy agents and antibody-drug conjugates in development, perioperative NSCLC management has quickly become complicated with different pathways to perioperative treatment. Furthermore, circulating tumor DNA and studies looking at better tools to prognosticate immunotherapy response will help with decision-making regarding which patients should receive immunotherapy and if so, either only pre-operatively or both pre- and post-operatively. In this review, we look at the evolution of systemic therapy in the perioperative setting from adjuvant chemotherapy to adjuvant immunotherapy to perioperative immunotherapy and look at perioperative targeted therapy while looking ahead to future considerations.

3.
Lung Cancer (Auckl) ; 15: 129-133, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224878

RESUMO

On April 18, 2024, the Food and Drug Administration approved alectinib as an adjuvant treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) after tumor resection. This approval was grounded in the outcomes of the ALINA trial, which demonstrated that alectinib significantly enhances disease-free survival compared to traditional platinum-based chemotherapy in the adjuvant setting. The ALINA trial is notable not just for advancing ALK tyrosine kinase inhibitors (TKIs) into the adjuvant setting but also for its innovative approach of comparing them to adjuvant chemotherapy, distinguishing it from other landmark trials.

4.
Lung Cancer (Auckl) ; 15: 115-121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39011085

RESUMO

On December 22, 2023, the US Food and Drug Administration (FDA) approved the biologics license application for patritumab deruxtecan (HER3-DXd) for priority review. This treatment is aimed at adult patients with locally advanced or metastatic NSCLC with EGFR mutations, who have received at least two prior systemic therapies. Approval of patritumab deruxtecan would mark it as the first HER3 targeted therapy in the United States. This prioritization by the FDA is grounded in compelling results from the global Phase II HERTHENA-Lung01 trial, wherein HER3-DXd exhibited clinically meaningful efficacy, achieving a median progression-free survival (mPFS) of 5.5 months in patients with heavily treated EGFR-mutated NSCLC. A pivotal question remains: Is a mPFS of 5.5 months sufficient in the context of the evolving first-line landscape observed in the FLAURA-2 and MARIPOSA trials?

6.
Lung Cancer (Auckl) ; 15: 1-8, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38298470

RESUMO

Targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have revolutionized the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of resistance to EGFR TKIs especially the third generation TKIs such as osimertinib remains a major clinical challenge. As a broader strategy for combating resistance, several clinical trials have explored the efficacy of immune checkpoint inhibitors (ICIs)+chemotherapy in EGFR-mutated NSCLC. Until now, the ORIENT-31 and IMpower150 trials suggested that ICIs+ chemotherapy may be more effective than chemotherapy alone after failure of EGFR-TKIs (although ORIENT-31 was negative for overall survival [OS] and IMpower150 was a subset analysis, so the study was not powered to detect a difference); however, the CheckMate-722 trial yielded disappointing results. Thus, the results of this global trial KEYNOTE-789 were highly anticipated.

7.
Br J Cancer ; 130(1): 108-113, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38057396

RESUMO

BACKGROUND: Previous studies in the general population observed that compared with non-Hispanic White women, Pacific Islander and Black women have higher age-adjusted mortality rates from epithelial ovarian cancer (EOC), while Asian American patients have lower mortality. We investigated whether race and ethnicity is associated with differences in EOC survival in a United States Military population where patients have equal access to healthcare. METHODS: This retrospective study included women diagnosed with EOC between 2001 and 2018 among Department of Defense beneficiaries. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models adjusting for age and year of diagnosis, histology and stage. RESULTS: In our study population of 1230 invasive EOC cases (558 non-Hispanic White, 74 non-Hispanic Black, 73 Asian, 30 Pacific Islander and 36 Hispanic cases), 63% of the women died (all-cause death) after a mean = 4.8 years (SD = 4.1) of follow-up following diagnosis. Compared with non-Hispanic White cases, Asian cases had better overall survival, HR = 0.76 (95% CI = 0.58-0.98), whereas there were no differences in survival for other racial and ethnic groups. CONCLUSIONS: These findings highlight the need to investigate how differences in access to healthcare may influence observed racial and ethnic disparities for EOC.


Assuntos
Etnicidade , Neoplasias Ovarianas , Humanos , Feminino , Estados Unidos/epidemiologia , Carcinoma Epitelial do Ovário , Estudos Retrospectivos , Disparidades em Assistência à Saúde , Brancos
8.
Front Oncol ; 13: 1240405, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38094606

RESUMO

Primary pancreatic malignancies are mostly composed of the adenocarcinoma histological subtype. However, squamous cell carcinoma (SCC) accounts for approximately 0.5%-1% of all malignant pancreatic cancers. Because of the rarity of SCC of the pancreas, guideline-directed treatment is lacking, treatment response is difficult to access, and treatment options are poorly defined. Here, we report a case of a 65-year-old man diagnosed with pancreatic carcinoma with dominant squamous cell differentiation, who achieved complete pathologic response (CPR) after treatment with gemcitabine, cisplatin, and nab-paclitaxel every 14 days for six cycles and who continues to lead a high quality of life 7 months later. To our knowledge, this is the first case of CPR in a case of SCC of the pancreas. To highlight the ambiguity and the need for further studies, we also performed a narrative review analyzing recent cases and compared them to our case.

9.
Acta Haematol ; : 1-7, 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-38059378

RESUMO

INTRODUCTION: Nirmatrelvir/ritonavir (NIM/r) inhibits tacrolimus metabolism resulting in a profound drug-drug interaction that is further complicated by the use of azole antifungals. CASE PRESENTATIONS: We describe three strategies, in 4 patient cases, for the initiation of NIM/r in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients on tacrolimus at the time of diagnosis. Patients 1 and 2 (strategy 1) experienced prolonged, elevated tacrolimus concentrations after an empiric 33% reduction in tacrolimus dose and adjustment of azole antifungal at NIM/r initiation (strategy 1) and with complete discontinuation of tacrolimus and azole antifungal at NIM/r initiation (strategy 2). Patients 3 and 4 (strategy 3) did not experience elevated tacrolimus concentrations on NIM/r treatment with complete discontinuation of tacrolimus and azole antifungal and a 12-24-h delay in NIM/r initiation. Reinitiation of tacrolimus after NIM/r completion resulted in variable tacrolimus concentrations. CONCLUSION: NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.

10.
Cancer Causes Control ; 34(11): 1017-1025, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37436537

RESUMO

PURPOSE: There are racial and ethnic differences in endometrial cancer incidence and mortality rates; compared with Non-Hispanic White women, Black women have a similar incidence rate for endometrial cancer, but their mortality is higher. Pacific Islander women may also have worse outcomes compared to their White counterparts. We assessed tumor characteristics and adjuvant therapy by racial and ethnic group among endometrial cancer patients treated within the Military Health System, an equal access healthcare organization. METHODS: We retrospectively identified women diagnosed with invasive endometrial cancer among US Department of Defense beneficiaries reported in the Automated Central Tumor Registry database (year of diagnosis: 2001-2018). We compared tumor characteristics and receipt of adjuvant therapy across racial and ethnic groups using Chi-square or Fisher tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of all cause mortality were calculated using Cox proportional hazards regression models adjusting for age at diagnosis, adjuvant therapy, histology and stage. RESULTS: The study included 2574 endometrial cancer patients [1729 Non-Hispanic White, 318 Asian, 286 Black, 140 Pacific Islander and 101 Hispanic women]. Among all cases, a higher proportion of Black patients had non-endometrioid histology (46.5% versus ≤ 29.3% in other groups, P < 0.01) and grade 3-4 tumors (40.1% versus ≤ 29.3% in other groups, P < 0.01). In multivariable Cox models, compared with Non-Hispanic White cases, Black endometrial cancer patients had a higher mortality risk (HR 1.43, 95% CI, 1.13-1.83). There was no difference in mortality risk for other racial and ethnic groups. CONCLUSION: Black patients with endometrial cancer presented with more aggressive tumor features and they had worse overall survival compared with patients in other racial and ethnic groups. Further study is needed to better direct preventive and therapeutic efforts in order to correct endometrial cancer disparities in the future.

11.
Am J Case Rep ; 24: e939448, 2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37381599

RESUMO

BACKGROUND Microsatellite instability (MSI) is a hallmark of specific cancers and can be diagnosed using both tissue- and liquid-based approaches. When these tissue- and liquid-based approaches give differing results, they are known as discordant or being at variance. MSI-H tumors are well-researched candidates for treatment with programmed cell death protein 1 (PD-1) inhibitor-based immunotherapy, but the efficacy of immunotherapy in MSI-H discordant endometrial cancer, especially as first-line therapy, is not yet well documented in the literature. CASE REPORT A 67-year-old woman presented with a retroperitoneal mass positive for recurrent adenocarcinoma of endometrial origin. Her stage I endometrial adenocarcinoma 7 years ago demonstrated microsatellite stable (MSS) by immunohistochemical (IHC) stain and indeterminant due to insufficient tissue by Caris Next-Generation Sequencing (NGS). She then presented with a retroperitoneal mass that was MSI-H on IHC stain and Caris NGS, as well as MSI high on liquid biopsy @Guardant360 (@G360). The patient proceeded with pembrolizumab treatment 1 year ago and has sustained a complete clinical response at the time of writing. CONCLUSIONS Our case provides further evidence for the need to retest the microsatellite stability of metastatic sites, especially after a long disease-free survival. Here, we providing a literature review of case reports and a review of studies outlining discordance of testing modalities. Our case also highlights the importance of considering the use of immunotherapy as a first-line agent in patients who may have a poor ECOG performance status, as it can significantly improve their quality of life and reduce the number of adverse effects compared to chemotherapy.


Assuntos
Adenocarcinoma , Qualidade de Vida , Feminino , Humanos , Idoso , Recidiva Local de Neoplasia , Repetições de Microssatélites , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética
12.
Lung Cancer (Auckl) ; 13: 75-80, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387582

RESUMO

KRASG12C is one of the most common oncogenes in non-small cell lung cancer (NSCLC) and is associated with a poor prognosis. Historically, KRAS mutations have been difficult to target due to lack of binding sites and exceptionally high affinity for guanosine triphosphate/guanosine diphosphate (GTP/GDP). Recently, KRASG12C selective inhibitors have shown promising results in Phase I/II studies. Here we discuss the mechanism of action, pharmacokinetic and pharmacodynamic properties, efficacy, and tolerability of adagrasib (MRTX849).

13.
Hawaii J Health Soc Welf ; 80(12): 295-297, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34877541

RESUMO

Both Hodgkin's lymphoma and testicular cancers can present in young men; however, concurrent Hodgkin's lymphoma with seminoma is very rare. When they do coexist, careful consideration must be made to avoid missing new cancer by assuming the presence of primary metastatic disease when lymphadenopathy presents. Here we present a rare case of coexistence of seminoma and Hodgkin's lymphoma and the staging and treatment challenges associated with a 2-cancer diagnosis.


Assuntos
Doença de Hodgkin , Seminoma , Neoplasias Testiculares , Havaí/epidemiologia , Doença de Hodgkin/complicações , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Masculino , Seminoma/complicações , Seminoma/diagnóstico , Neoplasias Testiculares/complicações , Neoplasias Testiculares/patologia , Neoplasias Testiculares/terapia
14.
Hawaii J Health Soc Welf ; 80(8): 190-194, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34355195

RESUMO

Chronic cough has a broad differential, and thoracic aortic aneurysm (TAA) is a rare but potentially life-threatening etiology. We present a giant arch TAA in a non-dyspneic, Pacific Islander man with significant tobacco-use history who presented with chronic cough with no acute pulmonary process noted on imaging. Given the high mortality rates associated with thoracic aortic aneurysms, the purpose of this report is to highlight the importance of keeping TAA as a rare differential for chronic cough, particularly when caring for patients with elevated risk. Recognition of patients with thoracic aortic disease who have a class I indication for surgical intervention (meaning there is evidence or general agreement that surgery will be beneficial, useful, and effective) as well as prompt evaluation of their anatomical landmarks in the perioperative period is critical. Imaging and, in particular, computed tomography remain the optimal modalities to screen for thoracic aortic disease.


Assuntos
Aneurisma da Aorta Torácica , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/cirurgia , Tosse/etiologia , Humanos , Masculino , Fatores de Risco , Tomografia Computadorizada por Raios X
17.
Case Rep Oncol Med ; 2019: 2305315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308983

RESUMO

We present a case of recurrent, platinum-refractory undifferentiated carcinoma of the parotid which was treated with checkpoint inhibitor, Pembrolizumab, and achieved a complete response to therapy. We review the literature of checkpoint inhibitor use in undifferentiated carcinoma of the parotid.

18.
Respir Med Case Rep ; 27: 100825, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30963023

RESUMO

Electronic cigarette (e-cigarette) use, or vaping, is gaining widespread popularity among adults aged 18-35. Vaping is commercially promoted as a safer alternative to traditional cigarette smoking. Previous studies have reported a close relationship between conventional cigarette smoking and acute eosinophilic pneumonia (AEP), but only one case report to date associates vaping with AEP in a male patient. We present the first case of AEP involving a young female after use of e-cigarettes. Clinicians should consider AEP when evaluating young patients with hypoxic respiratory failure and a recent history of e-cigarette use. This case highlights the need for more research into the relationship between e-cigarettes and AEP.

19.
Gastroenterology ; 156(8): 2297-2312, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30836096

RESUMO

BACKGROUND & AIMS: Interleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans. METHODS: B6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c+ or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c+ cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses. RESULTS: GNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4+ DCs and MDSCs; and decreased numbers of CD8+ DCs. IL6 was mainly produced by CD4+/CD11b+, but not CD8+, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c+ cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival. CONCLUSIONS: GNAI1;3 suppresses DSS-plus-AOM-induced colon tumor development in mice, whereas expression of GNAI2 in CD11c+ cells and IL6 in CD4+/CD11b+ DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.


Assuntos
Transformação Celular Neoplásica/genética , Colite/patologia , Neoplasias do Colo/patologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Animais , Biópsia por Agulha , Carcinogênese , Colite/genética , Neoplasias do Colo/genética , Modelos Animais de Doenças , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Imuno-Histoquímica , Interleucina-16/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Valores de Referência , Sensibilidade e Especificidade , Transdução de Sinais/genética
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